Adenine and uridine nucleotides induce pharmacological and physiological responses through several G-protein-coupled receptors (P2Y) and ligand-gated cation channels (P2X) (1, 2). The P2Y family encompasses two selective purinoceptors: the human P2Y1 and P2Y11 receptors which are preferentially activated respectively by ADP and ATP (3-5). Nucleotide receptors responsive to both adenine and uracil nucleotides are the P2Y2 receptor, activated equipotently by ATP and UTP (6, 7) as well as the Xenopus P2Y8 (8) and turkey tp2y receptor (9) activated equally by all triphosphate nucleotides. There are also pyrimidinoceptors: the chicken P2Y3 (10) and human P2Y6 (11-13) receptors activated preferentially by UDP, and the human P2Y4 receptor (13-15) activated preferentially by UTP. All these P2Y subtypes are coupled to the phosphoinositide pathway. The P2Y11 and tp2y receptors are additionally coupled respectively to stimulation and inhibition of adenylyl cyclase. Other receptors (P2Y5 (16), P2Y7 (17), P2Y9 and P2Y10) have been mistakenly included in the P2Y family (18-20). Recently, a P2Y12 subtype has been cloned which corresponds to the platelet ADP receptor previously called P2T (21, 22). It is coupled to an inhibition of adenylyl cyclase and is specifically expressed in the platelets and the brain. Its primary structure is not related to the other P2Y receptors but is related to that of the UDP-glucose receptor (23).
More than 300 G protein coupled receptors (GPCRs) have been cloned thus far and it is generally assumed that well over 1000 such receptors exist. Mechanistically, approximately 30-50% of all clinically relevant drugs act by modulating the functions of various GPCRs (34).
Known and unknown GPCRs now constitute major targets for drug action and development.
GPR86 is a member of the rhodopsin-like receptor family, cloned in 1997 (24). It shows a homology of 49% with the recently identified platelet ADP receptor, P2T.
The identified ORF of 1002 bp of said receptor is preceded by a stop codon 18 bp upstream, and the putative poly(A) signal AATAAA is present 1672 bp downstream of the coding sequence. hGPR86 has the same genomic localization as hGPR87 on chromosome 3q24, but in contrast to hGPR87, its coding sequence is intronless. The deduced 333 amino acid residue sequence of hGPR86 shows the typical 7 transmembrane (7TM) structure of a GPCR, with no signal peptide. It exhibits essentially the same motifs as described for GPR87 and KIAA0001, and therefore is also a member of family 1 GPCRs. Instead of the DRY motif there is a DRF motif present which is also seen in the sequences of purinergic receptors, the C5A and Bonzo receptors, and the thrombin receptor precursors.